Project 3: Fyn Kinase Inhibitors and Alcohol Drinking Behaviors in Heavy Drinkers Suchitra Krishnan-Sarin, Ph.D. Abstract Historically, development of successful treatments for substance use disorders, including alcohol drinking, has been based on an understanding of the neurochemical mechanisms mediating the condition. CTNA4 has a novel and translational focus on understanding the role of an intracellular signaling mechanism, related to protein tyrosine phosphatases, in mediating alcohol induced disturbances in DA and glutamate signaling, and the relevance of these interactions to alcohol reward and drinking and alcohol habits. This project, P3, which is an important component of the translational CTNA4, will evaluate if a Fyn Kinase inhibitor, Saractinib, alters drinking behavior in heavy drinkers. Saractinib is a Fyn Kinase inhibitior developed by Astra Zeneca that will target NMDA receptor signaling and has been used in multiple studies with healthy control, patients with solid tumors and patients with Alzheimers disease. P3 is inherently innovative in both its conception and application because it identifies an important gap in clinical knowledge ?how to target NMDA receptor function to reduce drinking without increasing positive alcohol effects- and then brings to bear an experiment which combines a novel therapeutic agent and a behavioral science tool, the Alcohol drinking paradigm (ADP) to investigate this question. The project is served by the cores but also supports the goals of the CTNA cores, including the clinical and translational cores, to ask unique questions like the role of ?habit? and novel neuroimaging markers in predicting medication response. P3 will address the primary questions of whether Fyn kinase inhibition with Saractinib, alters alcohol drinking and craving in heavy drinkers using the ADP. It will also evaluate if Saracatinib alters alcohol effects like stimulation and sedation and examine various novel predictors of treatment response including habit, impulsivity, deficiencies in learning in response to rewards/punishment and neuroimaging markers of functional brain connectivity.